Differential structural alterations and expression of immunoglobulin (Ig), T cell receptor (TCR), and various growth effecting genes are studied in malignant tumors and their derivative cell types. Studies are carried out to diagnose, classify, and stage lymphoid malignancies via a) Southern and Northern blot analysis and b) RNA-RNA tissue in situ hybridization. a)DNA and RNA is extracted from the tumors of patients with acute lymphoblastic leukemia (ALL) of infancy, pre B ALL, T cell ALL, mycosis fungoides, and Sezary syndrome. The structural reconfigurations of DNA around the Ig and TCR loci resulting from the normal functional activation of these loci in these cells provide unique "fingerprints" for identifying clonal populations in the samples and following these populations during the course of treatment. We have shown by these analyses that the above listed lymphoid malignancies each manifest generally distinguishing genotypic patterns reflecting target cell maturation which to a certain extent recapitulates the age incidence of the development of these tumors. b) RNA-RNA tissue in situ hybridization. The expression of individual cells within tissue sections from lymph node biopsies and peripheral blood from patients with lymphoid malignancies have been analyzed with immunoglobulin, T cell receptors, and oncogene probes. This technique refines the analysis of such tissue to the point where the unique gene expression of one cell in hundreds of thousands can be identified. Applying this technique to patients with CLL has revealed an unexpected cellular heterogeneity in the involved tissues. Analyses of patients with Hodgkin's disease is beginning to shed light on the origin and role of the different cell types (including the Reed- Sternberg cell) in this disease. The research and clinical utility of this technique is profound and it can be as easily and systematically applied as are current histochemical and immunocytochemical techniques.